Injection shut off valve with pressure actuator for delivery of compositions

ABSTRACT

Injection shut off valve devices and methods are provided for limiting flow and pressure from a pharmaceutical composition on injection. In some embodiments, the injection shut off valve is coupled to a syringe and can be used to monitor and avoid maximum pressures that can cause damage on injection.

BACKGROUND

During the course of medical treatment, it is often necessary to deliverpharmaceutical compositions (e.g., tissue bulking materials, bonefillers, contrast agents, drugs, growth factors, etc.) to a targettissue site by injection. In general, a hollow needle or cannula with asyringe attached to it is inserted at or near the target tissue and thepharmaceutical composition delivered. At the time of injection, pressureis exerted in the syringe to expel the pharmaceutical composition at ornear the target tissue site.

Sometimes, particularly with viscous compositions, such as for example,in situ setting materials, gels, bone cements, and other pharmaceuticalcompositions, the practitioner will exert excessive pressure to expelthe pharmaceutical composition from the needle or cannula. Thisexcessive pressure may rupture the target tissue causing damage to thetissue and/or leakage of beneficial physiological fluid. For example,when treating a spinal disc annular tear or herniation, the practitionerwill often administer an in situ setting material at or near the site ofthe disc injury. If the in situ setting material is administered underexcessive pressure, this can cause further trauma to the disc area bycausing the nucleus pulposus (the jelly-like substance in the middle ofthe spinal disc) to leak out of the annulus fibrosus (the fibrous ringof the intervertebral disc) leading to further annulus tearing orherniation and/or painful debilitating effects on the patient bycompressing the spinal canal and the spinal nerve root.

The pain from the annular tear or herniated disc may be furtherexacerbated as the nucleus pulposus contains significant amounts ofsubstances capable of exciting, or increasing the excitability of,sensory nerves such as prostaglandin E, histamine-like substances,lactic acid and polypeptide amines. These substances may also escapeincreasing the lower back pain or cause radiating leg pain. In addition,the increased pressure from the injection may increase the size of anyannular tear present in the disc, which may cause fibrous tissue to growinto the tear, which also increases pain and/or inflammation.

Excessively high pressure injections can damage other tissues such asblood vessels causing blood and/or the pharmaceutical composition toleak into surrounding tissues that are not intended to be the target ofthe therapy. This may also cause pain, inflammation, edema, scars andoften times, necrosis of the surrounding tissue or even an embolism.

High pressure injections may also lead to the practitioner giving toomuch of the pharmaceutical composition too soon which can be detrimentalto the patient due to adverse effects of the sudden dose of thepharmaceutical composition. For example, sudden administration ofpharmaceutical compositions can cause fluid overload at or near thetarget tissue site, which may cause edema, hypertension, electrolyteimbalance, or in severe case heart failure. This is particularly so whenadministering very potent pharmaceutical compositions that have a lowtherapeutic index, even small quantities administered too soon to thepatient can be detrimental.

Sometimes, if too much pressure is used to expel the pharmaceuticalcomposition from the syringe, the composition may migrate away from thetarget tissue site leading to reduced efficacy of the composition oreven damage to surrounding tissue. For example, when using bone cementsor fillers that are administered in a flowable state and later hardenafter administering them at a target tissue site, if the bone cement orfiller is expelled from the needle or cannula at an excessive pressure,it may migrate to surrounding tissue and harden in the wrong area (e.g.,such as a healthy joint or vertebrae) which may severely inhibitmovement of the joint. In more severe cases, the bone cements or fillersmay migrate to a blood vessel and cause an ischemic event (e.g.,embolism, necrosis, edema, infarction, etc.), which could be detrimentalto the patient.

In light of this background, there exist needs for improved devices andmethods for injecting pharmaceutical compositions at or near a targettissue site.

SUMMARY

Devices and methods are provided that allow delivery of thepharmaceutical composition (e.g., tissue bulking materials, bonecements, fillers, contrast agents, drugs, growth factors, etc.) at ornear a target tissue site without exceeding a maximum pressure that cancause damage to tissue at or near the target tissue site. One advantageof the embodiments provided herein is that by utilizing an injectionshut off valve that prevents flow of the pharmaceutical composition whena maximum pressure is reached, the practitioner can administer thecomposition where the risk of damage to the tissue resulting from highpressure injections is reduced or eliminated. Another advantage of thedevices and methods of the present application is that accurate doses ofthe pharmaceutical composition can be delivered via injection.

In one embodiment, an injection shut off valve for limiting flow of acomposition is provided, the shut off valve comprising: a housing havingan inlet, an outlet and a flow path disposed therebetween and in fluidcommunication with the inlet and the outlet, the inlet configured toreceive an end of an injection syringe; and a valve assembly contactingthe flow path and having a first chamber and a second chamber, the firstchamber comprising a diaphragm movable in at least a closed position toprevent flow of the composition to the outlet, the second chamber havingan actuator disposed therein, the actuator responsive to pressure in theflow path and coupled to the diaphragm in the first chamber, theactuator movable in at least an upper position when a select pressure isreached in the flow path, wherein movement of the actuator in the upperposition moves the diaphragm in the first chamber to the closed positionto prevent flow of the composition.

In a second embodiment, a device is provided for delivering apharmaceutical composition to a target tissue, the apparatus comprising:a syringe having a barrel, the barrel having a proximal end and a distalend, the barrel comprising a plunger being slidably receivable withinthe barrel to pressurize and expel the pharmaceutical compositioncontained in the barrel out the distal end of the barrel; a housingcoupled to the distal end of the barrel of the syringe and configured toreceive pressure and the composition from the barrel when the plunger isslid, the housing having an inlet, an outlet and a fluid path disposedtherebetween, the fluid path in fluid communication with the inlet andthe outlet; and a valve assembly disposed between the inlet and outletand contacting the fluid path and having a chamber comprising adiaphragm movable in at least a closed position to prevent flow of thecomposition to the outlet and an actuator disposed in the chamber, theactuator responsive to pressure in the fluid path and coupled to thediaphragm in the chamber, the actuator movable in at least an upperposition when a select pressure is reached in the fluid path, whereinmovement of the actuator in the upper position moves the diaphragm inthe chamber to the closed position to prevent flow of the composition.

In another embodiment, a method is provided for limiting or reducingpressure from a pharmaceutical composition on injection at or near atarget tissue site, the method comprising injecting the pharmaceuticalcomposition at or near the target tissue site using a syringe having abarrel, the barrel having a proximal end and a distal end, the barrelcomprising a plunger being slidably receivable within the barrel topressurize and expel the pharmaceutical composition contained in thebarrel out the distal end of the barrel; a housing coupled to the distalend of the barrel of the syringe and configured to receive pressure andthe composition from the barrel when the plunger is slid, the housinghaving an inlet, an outlet and a fluid path disposed therebetween, thefluid path in fluid communication with the inlet and the outlet, a valveassembly disposed between the inlet and outlet and contacting the fluidpath and having a chamber comprising a diaphragm movable in at least aclosed position to prevent flow of the composition to the outlet and anactuator disposed in the chamber, the actuator responsive to pressure inthe fluid path and coupled to the diaphragm in the chamber, the actuatormovable in at least an upper position when a select pressure is reachedin the fluid path, wherein movement of the actuator in the upperposition moves the diaphragm in the chamber to the closed position toprevent flow of the composition.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a side plan view of an embodiment of a device fordelivering a pharmaceutical composition to a target tissue site, where asyringe is coupled to a housing having the valve assembly, which iscoupled to a delivery tube.

FIG. 2A illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm in an open positionand an actuator in a lower position that can connect to a syringe and/orcannula for delivery of the pharmaceutical composition.

FIG. 2B illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm in a closedposition and an actuator in an upper position to prevent flow of thepharmaceutical composition.

FIG. 3 illustrates a side plan view of an embodiment of a device fordelivering a pharmaceutical composition to a target tissue site, where asyringe is coupled to a housing having the valve assembly, which iscoupled to a delivery tube. The housing has a pressure gauge so thatpressure from the injection can be monitored.

FIG. 4A illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm in an open positionand an actuator in a lower position that can connect to a syringe and/orcannula for delivery of the pharmaceutical composition.

FIG. 4B illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm in a closedposition and an actuator in an upper position to prevent flow of thepharmaceutical composition.

FIG. 5 illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm in a closedposition and an actuator in an upper position to prevent flow of thepharmaceutical composition. Here the valve assembly is coupled to acomputerized displayed to measure pressure.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a chamber” includes one, two, three or more chambers.

The term “at or near” is intended to include a region extending up toand including from 0 cm to 5 cm from the target tissue site (e.g.,nerve, muscle, ligament, bone, vertebra, etc.), as well as interiorregions within the target tissue site.

The term “spine” includes neuronal, bony, vascular and soft tissuecomponents. This includes the vertebral bodies and their associatedjoints (facets, costovertebral joints, or disc interfaces), theintervertebral discs, the intrinsic musculature, the spinal cord, spinalnerves, sympathetic nerves or ganglia associated with the axialskeleton, vertebral or disc innervations, and/or associated bloodvessels.

The term “axial” refers to the head, neck and/or back of a patient.

The term “disc” may be one or more discs within a spinal column,including cervical, thoracic or lumbar discs.

The term “disc region” is intended to include a region extending about 5cm from the surface of a disc, the surface of the disc, as well asinterior regions within the disc.

The term “degeneration” refers to anatomical signs of degeneration,which can include changes in the height of the disc, the level ofhydration of the disc, ruptured or contained herniation, annularbulging, and the presence of tearing or osteophytes. A reduction in theheight of the disc may be one of the most common, early and easilydetectable changes present in a degenerating disc. Another sign ofdegeneration is normally the loss of the T2 weighted signal on an MRIscan; this is indicative of a loss of hydration of the nuclear tissue.The degeneration can be a contained disc that occupies the spacedetermined by the size of the endplates or a herniated disc. Herniationcould be of a contained nature called, for example, bulging of the discor a herniated disc can also be ruptured with release of discalelements, such as the nucleus pulposus, outside the disc. Signs ofdegeneration such as inflammation, tissue density, changes in pH,increased innervation and vascularization can also be found adjacent tothe disc.

The term “surgical procedure” includes a procedure in which one or moreincisions are made into the body in order to repair damage or removediseased tissue.

The term “spinal surgery” includes a procedure in which one or moreincisions are made and requires manipulation of spinal tissues, with orwithout removal and/or repair of spinal tissues. Examples of spinalsurgery include, but are not limited to, repair of a herniated disc,adhesioloysis, radiofrequency neurotomy; intradiscal electrothermaltherapy, fusion of vertebrae, full or partial discectomy, laminectomy,laminotomy, or laminoplasty, or the like.

The term “practitioner” means a person who is using the methods and/ordevices of the current disclosure on the patient. This term includes,without limitation, doctors (e.g., surgeons, interventional specialists,physicians), nurses, nurse practitioners, other medical personnel,clinicians, veterinarians, or scientists.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc. In various embodiments, the mammal is a human patient.

The term “fluid communication” includes that the pharmaceuticalcomposition (e.g., liquid, solid, semi-solid) and/or pressure is indirect or indirect connection. Thus, for example, if the inlet is influid connection with the flow path, the connection may be through adirect connection, or through an indirect connection via other devicesand connections.

The term “implantable” as utilized herein refers to a pharmaceuticalcomposition (e.g., drug depot) retaining potential for successfulplacement within a mammal.

“Localized delivery” includes delivery of the pharmaceutical compositionat or near the target tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 5cm, or preferably within about 2 cm, or within about 1 cm, or less forexample) thereto. In some embodiments, localized delivery includes alsodelivering a drug depot locally to the target tissue site.

The term “pharmaceutical composition” as used herein is intended to haveits broadest possible interpretation and is used to include any agent,or substance that when delivered to the body of a living being has adesired, usually beneficial, effect. Pharmaceutical substances includebiologicals (.e.g., growth factors), drugs, carriers, tissue scaffolds,bulking material (e.g., bulking agents, sealers, in situ settingmaterials, gels, cements, etc.), or combinations thereof or the like.

Device for Delivery of the Composition

In some embodiments, a device is provided for delivering apharmaceutical composition to a target tissue, the apparatus comprising:a syringe having a barrel, the barrel having a proximal end and a distalend, the barrel comprising a plunger being slidably receivable withinthe barrel to pressurize and expel the pharmaceutical compositioncontained in the barrel out the distal end of the barrel; a housingcoupled to the distal end of the barrel of the syringe and configured toreceive pressure and the composition from the barrel when the plunger isslid, the housing having an inlet, an outlet and a fluid path disposedtherebetween, the fluid path in fluid communication with the inlet andthe outlet; and a valve assembly disposed between the inlet and outletand contacting the fluid path and having a chamber comprising adiaphragm movable in at least a closed position to prevent flow of thecomposition to the outlet and an actuator disposed in the chamber, theactuator responsive to pressure in the fluid path and coupled to thediaphragm in the chamber, the actuator movable in at least an upperposition when a select pressure is reached in the fluid path, whereinmovement of the actuator in the upper position moves the diaphragm inthe chamber to the closed position to prevent flow of the composition.

FIG. 1 illustrates a side plan view of an embodiment of a device fordelivering a pharmaceutical composition to a target tissue site, where asyringe 28 is coupled to a housing 40 having the valve assembly, whichis coupled to a delivery tube 41.

The syringe 28 is generally cylindrical and has barrel 24 to hold andseal the pharmaceutical composition in a specific area within it at 12.The syringe has an opening near coupling 20 to allow the pharmaceuticalcomposition to be expelled from it. The syringe has plunger 32 that whenforce is applied to it (manually or automatically) the plunger 32 slideslongitudinally forward in the direction of coupling 20. The plunger willpressurize barrel 24 and the specific area 12 and expel thepharmaceutical composition into the housing 40 (having the valveassembly) out past coupling 38 to dispensing tube 41 and out to thetarget tissue site. This is provided that the maximum pressure for theinjection is not reached. The syringe may have handle 30 to grasp andhold rim 23 as the practitioner slides the plunger 32 longitudinallyforward to expel the pharmaceutical substance from the barrel 24 toexpel it out past coupling 20 into housing 40. The housing 40, coupling20 are in fluid communication with the barrel 24 and the housing 40 andhousing coupling 38 are in fluid communication with flexible tubing 41.The housing coupling 20 can be any means including threading, reversethreading, mating pairs, leur fittings, etc. that allow the syringe tobe coupled to the housing 40. Likewise, the housing coupling 38 can beany means including threading, reverse threading, mating pairs, leurfittings, etc. that allow the tube or needle or cannula to be coupled tothe housing 40. The device of the present application can be all be inone unit pre-assembled or it can be assembled by taking a standardsyringe and coupling it to housing 40 at coupling 20 and then a standardneedle, cannula or tubing may be coupled to housing at 38 and theapparatus will be ready for delivery of the pharmaceutical composition.

The sidewall of the barrel 24 of the syringe 28 may be graduated orotherwise marked so as to gauge the position of the plunger 32 along thebarrel.

In one embodiment, an injection shut off valve for reducing flow of apharmaceutical composition is provided, the shut off valve comprising: ahousing having an inlet, an outlet and a flow path disposed therebetweenand in fluid communication with the inlet and the outlet, the inletconfigured to receive an end of an injection syringe; and a valveassembly contacting the flow path and having a first chamber and asecond chamber, the first chamber comprising a diaphragm movable in atleast a closed position to prevent flow of the composition to theoutlet, the second chamber having an actuator disposed therein, theactuator responsive to pressure in the flow path and coupled to thediaphragm in the first chamber, the actuator movable in at least anupper position when a select pressure is reached in the flow path,wherein movement of the actuator in the upper position moves thediaphragm in the first chamber to the closed position to prevent flow ofthe composition.

FIG. 2A illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm 50 shown in an openposition and an actuator 56 in a lower position that can connect to asyringe and/or cannula (not shown) for delivery of the pharmaceuticalcomposition. More particularly, the injection shut-off valve has ahousing 40, inlet line 42 and outlet line 44. A flow path connectinginlet line 42 to outlet line 44 shown as 43 and 49 is disposed betweenthe inlet line 42 and outlet line 44 and allows flow of thepharmaceutical composition (e.g., liquid, semi-solid, solid particles,etc.) to the outlet line 44, when certain pressure is reached in thevalve assembly. For example, pressure generated from the practitionersliding the plunger (32 in FIG. 1) in a forward direction increases thepressure in the barrel (24 in FIG. 1) to expel the pharmaceuticalcomposition out beyond the coupling (20 in FIG. 1) and into inlet 42.The pharmaceutical composition will flow along flow path 43 whendiaphragm 50 is in the open position as shown. Diaphragm 50 is in afirst chamber 46 that contacts the flow path. The first chamber 46 hasan elastic member 48 (e.g., spring, coil, clip, track, rib, sponge,wire, cable, projection, etc.) which biases against a surface of thediaphragm 50. When a select pressure is reached, the lever contactingthe diaphragm at 55 is released and the elastic member will move thediaphragm 50 in the downward direction indicated by 52 to close the flowpath and stop flow of the pharmaceutical composition and pressure.

Diaphragm 50 is configured to contact a pressure sensitive actuator 56that is disposed in a second chamber 60 that also contacts the fluidpath 49. In the embodiment shown, the diaphragm 50 and actuator 56 aresubstantially perpendicular to the fluid path. Also shown in theembodiment, the diaphragm comprises a recess 55 that is in contact withthe actuator 56 via lever having pivot 59 and the lever contacts or ispart of the actuator. Shown is the lever contacting the actuator 56 athole 53. It will be understood by those of ordinary skill in the artthat the diaphragm 50 may have one or more snap fit members, recesses,projections, wings, internal and external threading, tracks, clips,cleats, etc. that allow the lever to attach to the diaphragm and/oractuator.

The second chamber 60 has an elastic member 58 (e.g., spring, coil,clip, track, rib, sponge, wire, cable, projection, etc.) which biasesagainst a surface of the actuator 56. The elastic member in both thefirst and second chambers can be set to a certain tension to allowmovement of the actuator 56 in an upward direction shown by the arrow 54depending on the pressure that is desired in the fluid path 49. Theactuator 56 will move in the upward direction 54 when a certain pressureis reached. This will then cause the lever to release the diaphragm atrecess 55 and the elastic member will expand and move the diaphragm 50in the closed position stopping flow of pressure and the pharmaceuticalcomposition.

For example, when injecting into a large vessel such as an artery, thediaphragm, lever, elastic member and/or actuator can be set to a largerpressure reflecting this type of injection site. In contrast, injectioninto a smaller vessel such as a vein or into a confined area, thediaphragm, lever, elastic member and/or actuator can be set to a lowerpressure reflecting this type of injection site.

In some embodiments, as the pressure in the first or second chamberreaches greater than or equal to 80 psi, 90 psi, 100 psi, 110 psi, 120psi, 130, psi, 140 psi, or 150 psi or higher, the diaphragm will move inthe closed position and stop flow of the pharmaceutical composition.

In some embodiments, as the pressure in the needle or cannula tipreaches greater than or equal to 10 psi, 11 psi, 12 psi, 13 psi, 14 psi,15 psi, 16 psi, 17 psi, 18 psi, 19 psi, or 20 psi or higher, thediaphragm will move in the closed position and stop flow of thepharmaceutical composition.

FIG. 2B illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly when maximum pressure is reached inthe flow path where the diaphragm 51 is shown in the closed positionthat prevents flow of the pharmaceutical composition out outlet 44 andan actuator 56 is moved in an upper position by the pressure and/orpharmaceutical composition. More particularly, the injection shut-offvalve has a housing 40, inlet line 42 and outlet line 44. A flow pathconnecting inlet line 42 to outlet line 44 shown as 43 is disposedbetween them. As the pressure and/or pharmaceutical compositionincreases in the flow path by the second chamber 60 of the actuator, theactuator is moved in an upper position shown as 57 by the pressureand/or pharmaceutical composition (e.g., pressure from the liquid,semi-solid, solid particles, etc.) in the flow path. The arrow 54 showsthe pressure and/or pharmaceutical composition moving the actuator up.The elastic member 58 is compressed by a surface of the actuator. Thelever of the actuator at 53 has pivot 59 which releases the diaphragm inthe first chamber at recess 55 causing elastic member 48 to expand andrelease diaphragm 51 into the flow path to prevent flow of thepharmaceutical composition and/or pressure in the flow path 43 and outoutlet 44. The lever is shown in its released position. There will be aback up of pressure and/or pharmaceutical composition at the inlet 42 ofthe housing. The practitioner will detect the backup pressure as theplunger that is inside the syringe barrel that is coupled to the housingat 20 will be difficult to push. Therefore, as the maximum pressure isreached in the flow path the valve assembly will shut down and thusdamage to tissue or leakage of the pharmaceutical composition to thesurrounding tissue will be avoided.

In some embodiments, the diaphragm is smaller, the same size or largerthan the flow path. In some embodiments, the diaphragm has the samediameter or a diameter that is larger than the flow path to stop flow ofpressure and/or flow of the pharmaceutical composition in the flow path.In some embodiments, the actuator is the same size, smaller and/orlarger than the flow path.

In some embodiments, the diaphragm comprises non-porous material toeffectively seal the flow path 43 from pressure and/or pharmaceuticalcomposition, when in the closed position. In some embodiments, theactuator 57 comprises non-porous material so that a more accuratemeasurement of pressure and/or pharmaceutical composition from the flowpath 49 can be made. In some embodiments, the diaphragm and/or theactuator comprises non-deformable material.

FIG. 3 illustrates a side plan view of an embodiment of a device fordelivering a pharmaceutical composition to a target tissue site, where asyringe 28 is coupled to a housing 40 having the valve assembly, whichis coupled to a delivery needle or cannula 18.

The syringe 28 is generally cylindrical and has barrel 24 to hold andseal the pharmaceutical composition in a specific area within it at 12.The syringe has an opening near coupling 20 to allow the pharmaceuticalcomposition to be expelled from it. The syringe has plunger 32 that whenforce is applied to it (manually or automatically) the plunger 32 slideslongitudinally forward in the direction of coupling 20. The plunger willpressurize barrel 24 and the specific area 12 and expel thepharmaceutical composition into the housing 40 (having the valveassembly and fluid path) out past coupling 38 to dispensing needle orcannula 41 and out to the target tissue site. This is provided that themaximum pressure for the injection is not reached.

The syringe may have handle 30, in manual injections, to grasp and holdrim 23 as the practitioner slides the plunger 32 longitudinally forwardto expel the pharmaceutical substance from the barrel 24 to expel itthrough out past coupling 20 into housing 40. The housing 40, coupling20 are in fluid communication with the barrel 24 and the housing 40 andhousing coupling 38 are in fluid communication with needle or cannula18. The housing coupling 20 can be any means including threading,reverse threading, mating pairs, leur fittings, etc. that allow thesyringe to be coupled to the housing 40. Likewise, the housing coupling38 can be any means including threading, reverse threading, matingpairs, leur fittings, etc. that allow the tube or needle or cannula tobe coupled to the housing 40. The apparatus can be all be in one unitpre-assembled or it can be assemble by taking a standard syringe,loading it with the composition, and coupling it to housing 40 atcoupling 20 and then a standard needle or tubing may be coupled tohousing at 38 and the apparatus will be ready for delivery of thepharmaceutical composition.

A side wall of the housing 34 has pressure gauge 36 that indicates thepressure. The pressure gauge is coupled to the diaphragm, lever, elasticmember and/or actuator so that as the pressure increases or decreasesand there is movement of diaphragm, lever, elastic member and/oractuator, the pressure gauge will move as well and indicate the pressurein the fluid path. The pressure gauge can be calibrated beforehandaccording to an expected pressure to be met when the injection is indeedadministered.

The sidewall of the barrel 24 of the syringe 28 may be graduated orotherwise marked so as to gauge the position of the plunger 32 along thebarrel.

FIG. 4A illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly having a diaphragm 50 shown in an openposition and an actuator 56 in a lower position that can connect to asyringe and/or cannula (not shown) for delivery of the pharmaceuticalcomposition. More particularly, the injection shut-off valve has ahousing 40, inlet line 42 and outlet line 44. A flow path connectinginlet line 42 to outlet line 44 shown as 43 and 49 is disposed betweenthe inlet line 42 and outlet line 44 and allows flow of thepharmaceutical composition (e.g., liquid, semi-solid, solid particles,etc.) to the outlet line 44, when certain pressure is reached in thevalve assembly. For example, pressure generated from the practitionersliding the plunger (32 in FIG. 1) in a forward direction increases thepressure in the barrel (24 in FIG. 1) to expel the pharmaceuticalcomposition out passed the coupling (20 in FIG. 1) and into inlet 42.The pharmaceutical composition will flow along flow path 43 whendiaphragm 50 is in the open position as shown. Diaphragm 50 is in afirst chamber 46 that contacts the flow path. The first chamber 46 hasan elastic member 48 (e.g., spring, coil, clip, track, rib, sponge,wire, cable, projection, etc.) which biases against a surface of thediaphragm 50. The elastic member will move the diaphragm 50 in thedownward direction indicated by 52 to close the flow path and stop flowof the pharmaceutical composition and pressure. Diaphragm 50 isconfigured to contact a pressure sensitive actuator 56 that is disposedin a second chamber 60 that also contacts the fluid path 49. In theembodiment shown, the diaphragm 50 and actuator 56 are substantiallyperpendicular to the fluid path. Also shown in the embodiment, thediaphragm is in contact with the actuator 56 at contact point 55 vialever having pivot 59 (there is no recess in the diaphragm in thisembodiment) and the lever contacts or is part of the actuator. Shown isthe lever contacting the actuator 56 at hole 53. It will be understoodby those of ordinary skill in the art that the diaphragm 50 may have oneor more snap fit members, recesses, projections, wings, internal andexternal threading, tracks, clips, cleats, etc. that allow the lever toattach to the diaphragm and/or actuator. The second chamber 60 has anelastic member 58 (e.g., spring, coil, clip, track, rib, sponge, wire,cable, projection, etc.) which biases against a surface of the actuator56. The elastic member in both the first and second chambers can be setto a certain tension to allow movement of the actuator 56 in an upwarddirection shown by the arrow 54 depending on the pressure that isdesired in the fluid path 49. As the pressure and/or pharmaceuticalcomposition increases in the flow path by the second chamber 60 of theactuator, the actuator is moved from a lower position to an upperposition by the pressure and/or pharmaceutical composition (e.g.,pressure from the liquid, semi-solid, solid particles, etc.) in the flowpath. The arrow 54 shows the pressure and/or pharmaceutical compositionmoving the actuator up. The elastic member 58 is compressed by a surfaceof the actuator. The lever of the actuator at 53 has pivot 59 whichmoves the diaphragm in the first chamber at 55 causing elastic member 48to expand and release diaphragm 50 into the flow path to prevent flow ofthe pharmaceutical composition and/or pressure in the flow path 43 andout outlet 44. The lever is shown in its unreleased position.

FIG. 4B illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly when maximum pressure is reached inthe flow path where the diaphragm 51 is shown in the closed positionthat prevents flow of the pharmaceutical composition out outlet 44 andan actuator 57 in an upper position. More particularly, the injectionshut-off valve has a housing 40, inlet line 42 and outlet line 44. Aflow path connecting inlet line 42 to outlet line 44 shown as 43 isdisposed between them. As the pressure and/or pharmaceutical compositionincreases in the flow path by the second chamber 60 of the actuator, theactuator is moved in an upper position shown as 57 by the pressureand/or pharmaceutical composition (e.g., pressure from the liquid,semi-solid, solid particles, etc.) in the flow path. The arrow 54 showsthe pressure and/or pharmaceutical composition moving the actuator up.The elastic member 58 is compressed by a surface of the actuator. Thelever of the actuator at 53 has pivot 59 which assists in moving thediaphragm in the first chamber at 55 causing elastic member 48 to expandand move diaphragm 51 into the flow path to prevent flow of thepharmaceutical composition and/or pressure in the flow path 43 and outoutlet 44. The lever is shown in its released position. There will be aback up of pressure and/or pharmaceutical composition. The practitionerwill detect the backup pressure as the plunger that is inside thesyringe barrel that is coupled to the housing at 20 will be difficult topush. Therefore, as the maximum pressure is reached in the flow path thevalve assembly will shut down and thus damage to tissue or leakage ofthe pharmaceutical composition to the surrounding tissue will beavoided.

In the embodiments shown in FIGS. 4A and 4B, the lever 59 contacts thediaphragm in such a way that as pressure increases, the diaphragm willmove gradually in increments downward and the actuator will move in thereciprocal direction (increments upward in response to the increasedpressure). In this way the flow of the pharmaceutical composition willgradually decrease in increments as pressure in the fluid pathincreases. If pressure exceeds the maximum pressure the diaphragm 51will completely block the fluid path and flow will stop.

Likewise, in the embodiments shown in FIGS. 4A and 4B, the lever 59contacts the diaphragm in such a way that as pressure decreases, thediaphragm will move in increments upward and the actuator will move inthe reciprocal direction (increments downward in response to thedecreased pressure). In this way, the flow of the pharmaceuticalcomposition will gradually increase in increments as pressure in thefluid path decreases.

FIG. 5 illustrates a side cross sectional view of an embodiment ofinjection shut off valve assembly when maximum pressure is reached inthe flow path where the diaphragm 51 is shown in the closed positionthat prevents flow of the pharmaceutical composition out outlet 44 andan actuator 57 in an upper position. In this embodiment, a computer 68is coupled to the diaphragm so that as the pressure increases ordecreases and there is movement of diaphragm, the pressure display 70will indicate the pressure in the fluid path.

More particularly, the injection shut-off valve has a housing 40, inletline 42 and outlet line 44. A flow path connecting inlet line 42 tooutlet line 44 shown as 43 is disposed between them. As the pressureand/or pharmaceutical composition increases in the flow path by thesecond chamber 60 of the actuator, the actuator is moved in an upperposition shown as 57 by the pressure and/or pharmaceutical composition(e.g., pressure from the liquid, semi-solid, solid particles, etc.) inthe flow path. The arrow 54 shows the pressure and/or pharmaceuticalcomposition moving the actuator up. The elastic member 58 is compressedby a surface of the actuator. The lever of the actuator at 53 has pivot59 which assists in moving the diaphragm in the first chamber at 55causing elastic member 48 to expand and move diaphragm 51 in a downwarddirection into the flow path to prevent flow of the pharmaceuticalcomposition and/or pressure in the flow path 43 and out outlet 44. Thelever is shown in its released position. There will be a back up ofpressure and/or pharmaceutical composition when the diaphragm 51 is inthe closed portion.

In the embodiments shown in FIG. 5, the diaphragm has two electricalcontact points 62 and 63, which contact two electrical leads 64 and 66coupled to computer 68. As the two contact points 62 and 63 of diaphragm51 contacts the electrical contact points, a pulse is generated inelectrical leads 64 and 66 to generate a pulse as shown in pressuredisplay 70. The practitioner will notice the peak in the display 70 andknow that maximum pressure in the flow path has been reached and theinjection and flow of the pharmaceutical will stop. It will beunderstood by those of ordinary skill in the art that one of moreelectrical contact points leading to the computer and display can bedisposed anywhere in the housing, for example, in the lever, elasticmember, flow path and/or actuator, as long as data can be sent to thecomputer 68 and shown on display 70. The computer may have data entrykeys 72 to calibrate the pressure sensitive actuator 57. There may bealso be data entry keys 74 to select the desired pressure that ifexceeded will cause the diaphragm to seal the flow path and preventdelivery of the pharmaceutical composition. There also may be data entrykeys to shut the apparatus off 76 or turn it on.

In some embodiments, the pressure for activation of the actuator and tostop flow can be set depending on factors, such as for example, the typeof composition, the duration of the injection, type of treatment, andthe type of tissue the cannula, needle, or tube will be placed at ornear. For example, the device can be set so that low pressure and/orpharmaceutical composition is given to the target tissue site at or nearthe spine (e.g., annulus, nucleus, facet capsule, nerve root, etc.).

In the embodiment shown in FIG. 5, the lever 59 contacts the diaphragmin such a way that as pressure increases, the diaphragm will movegradually in increments downward and the actuator will move in thereciprocal direction (increments upward in response to the increasedpressure). In this way the flow of the pharmaceutical composition willgradually decrease in increments as pressure in the fluid pathincreases. If pressure exceeds the maximum pressure the diaphragm 51will completely block the fluid path and flow will stop. Likewise, inthe embodiments shown in FIG. 5, the lever 59 contacts the diaphragm insuch a way that as pressure decreases, the diaphragm will move inincrements upward and the actuator will move in the reciprocal direction(increments downward in response to the decreased pressure). In thisway, the flow of the pharmaceutical composition will gradually increasein increments as pressure in the fluid path decreases. The pressure canbe monitored on display 70. Although the computer display is shown inFIG. 5 as separate, it will be understood by those of ordinary skill inthe art that the computer display can be one single unit and on one sideof the housing 40.

The device for injecting the pharmaceutical composition comprises acannula, needle and/or tubing that can be inserted through the skin to atarget tissue site at or near the spine (e.g., at an area comprising atleast one muscle, ligament, tendon, cartilage near the spine, or spinalnerve, spinal disc, spinal foraminal space near the spinal nerve root,facet or spinal canal). One advantage of the embodiments provided hereinis that by utilizing an injection shut off valve that prevents flow ofthe pharmaceutical composition when a maximum pressure is reached, thepractitioner can administer the composition where the risk of damage tothe tissue resulting from high pressure injections is reduced oreliminated. For example, when treating a spinal disc herniation, thepractitioner will often administer anti-inflammatory compositions at ornear the site of the disc herniation. If the anti-inflammatorycomposition is administered under excessive pressure, this can causefurther trauma to the disc area by causing the nucleus pulposus to leakout of the annulus fibrosus leading to further herniation and/or painfuldebilitating effects on the patient by compressing the spinal canal andspinal nerve root. By using the present apparatus, injections thatexceed a safe pressure are prevented as the diaphragm would prevent suchpressure from reaching the target tissue site to cause the furthertissue damage.

The cannula or needle or tubing of the device is designed to causeminimal physical and psychological trauma to the patient. Cannulas orneedles include tubes that may be made from materials, such as forexample, polyurethane, polyurea, polyether(amide), PEBA, thermoplasticelastomeric olefin, copolyester, and styrenic thermoplastic elastomer,steel, aluminum, stainless steel, titanium, metal alloys with highnon-ferrous metal content and a low relative proportion of iron, carbonfiber, glass fiber, plastics, ceramics or combinations thereof. Thecannula or needle or tube may optionally include one or more taperedregions. In various embodiments, the cannula or needle or tube may bebeveled. The cannula or needle or tube may also have a tip style vitalfor accurate treatment of the patient depending on the anatomical site.Examples of tip styles include, for example, Trephine, Cournand, Veress,Huber, Seldinger, Chiba, Francine, Bias, Crawford, deflected tips,Hustead, Lancet, or Tuohey. In various embodiments, the cannula orneedle or tube may also be non-coring and have a sheath covering it toavoid unwanted needle sticks.

In some embodiments, the cannula or needle or tube of the deliverydevice has a diameter that is the same size or smaller than the diameterof at least part of the plunger. In various embodiments, the diameter ofthe cannula or needle or tubing is substantially the same throughout. Inother embodiments, the diameter of the needle or cannula becomes smallerapproaching the distal end for delivery of the composition.

In some embodiments the cannula, needle, or tube is flexible. Theflexibility of the cannula, needle, or tube allows the device to bemaneuvered along a bend in the target tissue (e.g., the spine, muscle,joint, etc.). The flexibility of the cannula, needle, or tube allows theinjection locally to the target tissue site and is often dictated byanatomical consideration.

The dimensions of the hollow cannula or needle or tubing, among otherthings, will depend on the anatomic site for treatment. For example, thewidth of the epidural space is only about 3-5 mm for the thoracic regionand about 5-7 mm for the lumbar region. Thus, the needle or cannula ortubing, in various embodiments, can be designed for these specificareas. In various embodiments, the needle, cannula or tubing may beinserted using a transforaminal approach in the spinal foramen space,for example, along an inflamed nerve root and the pharmaceuticalcomposition injected at this site for treating the condition. Typically,the transforaminal approach involves approaching the intervertebralspace through the intervertebral foramina and injecting thepharmaceutical composition.

Some examples of lengths of the cannula or needle or tube may include,but are not limited to, from about 50 to 150 mm in length, for example,about 65 mm for epidural pediatric use, about 85 mm for a standard adultand about 110 mm for an obese adult patient. The thickness of thecannula or needle will also depend on the site of implantation. Invarious embodiments, the thickness includes, but is not limited to, fromabout 0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

The housing including elastic member, lever, diaphragm, actuator, flowpath, inlet, and outlet can be made from materials, such as for example,polyurethane, polyurea, polyether(amide), PEBA, thermoplasticelastomeric olefin, copolyester, and styrenic thermoplastic elastomer,steel, aluminum, stainless steel, titanium, metal alloys with highnon-ferrous metal content and a low relative proportion of iron, carbonfiber, glass fiber, plastics, ceramics or combinations thereof. Thehousing may optionally include one or more tapered regions to assist incoupling the barrel and/or cannula, needle, and/or tube thereto.

In some embodiments, the syringe includes a barrel and a plunger. Theplunger has a diameter less than the barrel so that it can be slidablyreceived therein. The plunger may be longer, shorter, the same size, orsmaller in length than the cannula or needle or tubing. Like thehousing, the plunger and barrel may be made from materials, such as forexample, polyurethane, polyurea, polyether(amide), PEBA, thermoplasticelastomeric olefin, copolyester, and styrenic thermoplastic elastomer,steel, aluminum, stainless steel, titanium, metal alloys with highnon-ferrous metal content and a low relative proportion of iron, carbonfiber, glass fiber, plastics, ceramics or combinations thereof.

The delivery device may be part or coupled to imaging devices used forradiography, fluoroscopy, luminescence, PET, SPECT, CT, MRI, and/orX-ray imaging techniques and display images as the cannula, needle, ortube is inserted at or near the target tissue site (e.g., at an areacomprising at least one muscle, ligament, tendon, cartilage near thespine, or spinal nerve, spinal disc, spinal foraminal space near thespinal nerve root, facet, annulus, or spinal canal, etc.).

Pharmaceutical Composition

The term “pharmaceutical composition” as used herein is intended to haveits broadest possible interpretation and is used to include any agent,or substance that when delivered to the body of a living being has adesired, usually beneficial, effect. Pharmaceutical substances includebiologicals (.e.g., growth factors), drugs, carriers, tissue scaffolds,bulking material (e.g., bulking agents, sealers, in situ settingmaterials, gels, cements, etc.), or combinations thereof or the like.

In various embodiments, the barrel, housing, cannula, needle, and/ortubing comprises a liquid, solid, or semi-solid pharmaceuticalcomposition that can be injected at the target tissue site. Thepharmaceutical composition is flowable. For example, the pharmaceuticalcomposition can be a flowable powder, liquid, or semi-solid (e.g., gel).

In some embodiment, the device limits the pressure that is allowed to beinjected at, near or in a tissue. For example, when dealing with painfuldegenerating intervertebral discs, the device will limit the pressurefrom flowable compositions such as silk, elastin, polyurethane, fibrinsealant, polyvinyl alcohol, sealants, in situ setting materials,cements, etc., which have no drugs but bulk up the disc to both increasedisc stability and seal any annular tears. If the practitioner injectswith too much pressure further damage can occur. The present devicelimits the pressure on injection and thus the risk of a highlypressurized injection is eliminated or reduced.

Representative classes of pharmaceutical compositions that can be usedin the present device include, e.g., trophic factors, analgesics,anti-inflammatory agents, anti-cancer agents, vaccines, adjuvants,antibodies, neuroleptics, genes and genetic elements for transfectionincluding viral vectors for gene therapy, cells or cellular components,etc. A list of more specific examples would therefore include, collagen,insoluble collagen derivatives, etc., soluble solids and/or liquidsdissolved therein, e.g., antiviricides, antimicrobials such aserythromycin, bacitracin, neomycin, penicillin, polymicin B,tetracyclines, biomycin, chloromycetin, and streptomycins,cephalosporins, ampicillin, azactam, tobramycin, clindamycin andgentamicin, etc.; biocidal/biostatic sugars such as dextran, glucose,etc.; amino acids, peptides, vitamins, inorganic elements, co-factorsfor protein synthesis; hormones; endocrine tissue or tissue fragments,synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.,polymer cell scaffolds with parenchymal cells, angiogenic drugs,polymeric carriers containing such drugs; collagen lattices; antigenicagents; cytoskeletal agents; cartilage fragments, modified living cellssuch as chondrocytes, bone marrow cells, mesenchymal stem cells, naturalextracts, genetically engineered living cells or otherwise modifiedliving cells, DNA delivered by plasmid or viral vectors, genes orgenetic elements, tissue transplants, demineralized bone powder,autogenous tissues such as blood, serum, soft tissue, bone marrow, bonesubstitutes, bone cements, etc.; bioadhesives; non-collagenous proteinssuch as osteoponfin, osteonectin, bone sialo protein, laminin,fibrinogen, vitronectin, thrombospondin, proteoglycans, decorin, betaglycan, biglycan, aggrecan, versican, tenascin, matrix gla protein,hyaluronan, amino acids, amino acid residues, peptides, bone morphogenicproteins (BMPs); osteoinductive factor (OIF); fibronectin (FN);endothelial cell growth factor (ECGF); cementum attachment extracts(CAE); ketanserin; human growth hormone (HGH); animal growth hormones;epidermal growth factor (EGF); interleukin-1 (IL-1); human alphathrombin; transforming growth factor (TGF-beta); insulin-like growthfactor (IGF-1) (IGF-2); platelet derived growth factors (PDGF);fibroblast growth factors (FGF, aFGF, bFGF, etc.); periodontal ligamentchemotactic factor (PDLGF); somatotropin; bone digestors; antitumoragents; immuno-suppressants; fatty acids (including polar and non-polarfatty acids); permeation enhancers, e.g., fatty acid esters such aslaureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives, alpha-keto-aldehydes, etc.; and nucleic acids;inorganic elements, inorganic compounds, cofactors for proteinsynthesis, hormones, soluble and insoluble components of the immunesystem; soluble and insoluble receptors including truncated forms;soluble, insoluble and cell surface bound ligands including truncatedforms; chemokines, bioactive compounds that are endocytosed; endocrinetissue or tissue fragments, growth factor binding proteins, e.g.,insulin-like growth factor binding protein (IGFBP-2) (IGFBP-4) (IGFBP-5)(IGFBP-6); angiogenic agents, bone promoters, cytokines, interleukins,genetic material, genes encoding bone promoting actions, cellscontaining genes encoding bone promoting action; growth hormones such assomatotrophin; bone digestors; antitumor agents; cellular attractantsand attachment agents; immuno suppressants; bone resorption inhibitorsand stimulators; angiogenic and mitogenic factors; bioactive factorsthat inhibit and stimulate secondary messenger molecules; cell adhesionmolecules, e.g., cell-matrix and cell-cell adhesion molecules; secondarymessengers, monoclonal antibodies specific to cell surface determinantson mesenchymal stem cells, clotting factors; externally expandedautograft or xenograft cells, nucleic acids or any combinations thereof.

The pharmaceutical composition that the device can deliver can be abulking or sealing agent. A wide variety of biocompatible polymericmaterials may be used as the bulking agent and/or sealing agent,including, but not limited to, silicon, polyurethane, copolymers ofsilicon and polyurethane, polyolefins, such as polyisobutylene andpolyisoprene, neoprene, nitrile, polyvinyl alcohol, acrylamides such aspolyacrylic acid and poly(acrylonitrile-acrylic acid), non-biologicallyabsorbable polyurethanes, polyethylene glycol,poly(N-vinyl-2-pyrrolidone), acrylates such as polyacrylates,poly(2-hydroxy ethyl methacrylate), methyl methacrylate, 2-hydroxyethylmethacrylate, and copolymers of acrylates with N-vinyl pyrrolidone,N-vinyl lactams, acrylamide, polyurethanes and polyacrylonitrile,glycosaminoglycans, collagen, polyethylene oxide, co-polymers of PVA andPVP, and combinations thereof. These materials may further becross-linked to provide further strength. Examples of polyurethanesinclude thermoplastic polyurethanes, aliphatic polyurethanes, segmentedpolyurethanes, hydrophilic polyurethanes, polyether-urethane,polycarbonate-urethane and silicon polyether-urethane. Other suitablehydrophilic polymers include naturally-occurring materials such asglucomannan gel, polyphosphazenes, hyaluronic acid, polysaccharides,such as cross-linked carboxyl-containing polysaccharides, alkylcelluloses, hydroxyalkyl methyl celluloses, sodium chondroitin sulfate,cyclodextrin, polydextrose, dextran, gelatin, and combinations thereof.Other suitable examples of biologically acceptable polymers includebiocompatible homopolymers and copolymers of hydrophilic monomers suchas 2-hydroxyalkyl acrylates and methacrylates, N-vinyl monomers, andethylenically unsaturated acids and bases; polycyanoacrylate,polyethylene oxide-polypropylene glycol block copolymers,polygalacturonic acid, polyvinyl pyrrolidone, polyvinyl acetate,polyalkylene glycols, polyethylene oxide, collagen, sulfonated polymers,vinyl ether monomers or polymers, alginate, polyvinyl amines, polyvinylpyridine, and polyvinyl imidazole.

One can also use superabsorbent polymers (SAP) with or withoutadditives. Superabsorbent polymers may include polymer chains that aresynthetic, natural, and hybrid synthetic/natural polymers. Exemplarysuperabsorbent polymers may include, but are not limited to, polyacrylicacid, polymethacrylic acid, polymaleic acid, copolymers thereof, andalkali metal and ammonium salts thereof; graft copolymers of starch andacrylic acid, starch and saponified acrylonitrile, starch and saponifiedethyl acrylate, and acrylate-vinyl acetate copolymers saponified;polyvinylpyrrolidone, polyvinyl alkylether, polyethylene oxide,polyacrylamide, and copolymers thereof; copolymers of maleic anhydrideand alkyl vinylethers; saponified starch graft copolymers ofacrylonitrile, acrylate esters, vinyl acetate, and starch graftcopolymers of acrylic acid, methyacrylic acid, and maleic acid; theproduct of crosslinking acrylamide with backbones of kappa-carrageenanand soldium alginate using methylenebisacrylamide and potassiumpersulfate; and the product of crosslinking, using a bifunctionalcrosslinking reagent, an acyl-modified protein matrix such as soyprotein isolate which has been acyl-modified by treatment withethylenediaminetetraacetic acid dianhydride; mixtures and combinationsthereof. Further, one can use silicon-based materials, polyethyleneterephthalate, polycarbonate, thermoplastic elastomers and copolymerssuch as ether-ketone polymers such as polyetheretherketone or acombination thereof. In some embodiments, the bulking and/or sealingagent can include any hydrostatic and/or hemostatic agents for sealing,(e.g., gelfoam), tissues, and/or proteins including collagen. In someembodiments, the bulking and/or sealing agent can be a superabsorbentpolymer (SAP). The SAP can be cross-linked to enhance its absorbencycapacity and gel strength. Superabsorbent polymers may include polymerchains that are synthetic, natural, and hybrid synthetic-naturalpolymers. Natural polymers include polysaccharides such as cellulose,starch, and regenerated cellulose that are modified to be carboxylated,phosphonoalkylated, sulphoxylated or phosphorylated, thereby causing thepolymer chains to become highly hydrophilic. Synthetic polymers that canbe used as SAP include, but are not limited to, polyacrylates. U.S. Pat.No. 5,147,343, U.S. Pat. No. 4,673,402, U.S. Pat. No. 5,281,207, andU.S. Pat. No. 4,834,735 disclose many types of SAPs and methods formaking them, and are incorporated herein by reference in their entiretyin accordance with the described embodiments.

In some embodiments, suitable bulking and/or sealing agents includecrosslinkable macromonomers that form hydrogels. These bulking and/orsealing agents macromers have a backbone of a polymer having units witha 1,2-diol and/or 1,3-diol structure. Such polymers include poly(vinylalcohol) (PVA) and hydrolyzed copolymers of vinyl acetate, for example,copolymers with vinyl chloride, N-vinylpyrrolidone, etc. The backbonepolymer may contain pendant chains bearing crosslinkable groups and,optionally, other modifiers. When crosslinked, the macromers formhydrogels advantageous for use as bulking and/or sealing agents fordifferent tissue types. Specific examples of bulking and/or sealingagents include microspheres formed from macromers, wherein the macromersprior to crosslinking have a polymeric backbone comprising units with a1,2-diol or 1,3-diol structure and at least two pendant chains bearingcrosslinkable groups which are olefinically unsaturated groups, whereinthe macromers are crosslinked via free radical polymerization to form ahydrogel. These types of polymeric bulking and/or sealing agents aredescribed in U.S. Pat. No. 6,652,883 and U.S. Pat. No. 7,070,809,assigned to BioCure, Inc. The entire disclosures of these patents areincorporated by reference herein.

Suitable bulking and/or sealing agents include a hydrogel formed from amacromer having a polymeric backbone comprising units with a 1,2-diol or1,3-diol structure and at least two pendant chains bearing crosslinkablegroups and an amphiphilic comonomer. The hydrogel can have a yield loadbetween about 1000 to 6000 Newtons or a compression modulus ofapproximately 3 mega pascals at 10-30% strain and the comonomer can bediacetone acrylamide (DAA), N-vinyl caprolactam,N-(butoxymethyl)acrylamide, N-acroyl morpholine, crotonamide,N,N-dimethyl acrylamide, N-octadecylacrylamide, acrylamide or acombination thereof. The hydrogel can have a macromer having apoly(vinyl alcohol) backbone with a molecular weight of about 14,000 andthe pendant chains bearing crosslinkable groups areN-acrylamidoacetaldehyde dimethyl acetal (NAAADA) in an amount of about6 to 21 crosslinkers per PVA. These types of polymeric bulking and/orsealing agents are described in U.S. Ser. No. 11/170,915, filed Jun. 29,2005 and published as US 2005/0288789 assigned to BioCure, Inc. Theentire disclosure of this patent application is incorporated byreference herein.

Suitable bulking and/or sealing agents can comprise macromers having abackbone comprising a polymeric backbone having units with a 1,2-diol or1,3-diol structure, such as polyvinyl alcohol, and pendant chainsbearing crosslinkable groups and, optionally, other modifiers. Whencrosslinked, the macromers form hydrogels that can seal and fill lumensand spaces, such as in an intervertebral disc. In some embodiments, thebulking and/or sealing agent can be crosslinked and form microspheres.In some embodiments, the polymeric backbone comprises a polyhydroxypolymer and the pendant chains bearing crosslinkable groups are attachedto the backbone via the 1,2-diol or 1,3-diol groups. In someembodiments, the pendant chains bearing crosslinkable groups areattached to the backbone via cyclic acetal linkages. These types ofpolymeric bulking and/or sealing agents are described in U.S. Pat. No.6,676,971, and U.S. Pat. No. 6,710,126, assigned to BioCure, Inc. Theseentire disclosures of these patents are incorporated by referenceherein.

Suitable bulking and/or sealing agents can comprise polymerizablecarbohydrate esters and polymers therefrom and homo- and co-polymershaving monomers with hydrophilic, amphiphilic or hydrophobic propertiesthat are able to form hydrogels, as described in U.S. Pat. No.5,571,882. The entire disclosure of this patent is incorporated byreference herein.

Suitable bulking and/or sealing agents can include membranes made fromamphiphilic copolymers. The amphiphilic copolymers can be ABAcopolymers, where one of A and B is hydrophilic and the other ishydrophobic. The copolymers may be crosslinked to form more stablestructures. Crosslinking can be accomplished using a variety of methods,including end to end polymerization of copolymers having terminalunsaturated groups as described in U.S. Pat. No. 6,723,814. The entiredisclosure of this patent is incorporated by reference herein.

Suitable bulking and/or sealing agents can be delivered to the site insitu at or near the damaged tissue and then gel in situ to form ahydrogel. These bulking and/or sealing agents include macromers havingwater soluble regions and crosslinkable regions as described in U.S.Ser. No. 09/960,449, filed Sep. 21, 2001 and published as US2002/0122771. This entire disclosure of this patent application isincorporated by reference herein.

The bulking and/or sealing agents can be incorporated into polymerichollow particles for delivery that change permeability in response to achange in an external stimulus such as pH, temperature, light, ionicstrength, electric field, magnetic field and/or solvent composition. Thehollow particles can have a shell formed of an amphiphilic triblock ABAor BAB copolymer, where A is a hydrophilic block and B is a hydrophobicblock, as described in U.S. Pat. No. 6,616,946, assigned to BioCure,Inc. The entire disclosure of this patent is incorporated by referenceherein.

In some embodiments, the pharmaceutical composition comprises a carriermatrix for implantation in a bone defect. The carrier matrix, whenplaced in a bone defect, provides scaffolding around which the patient'snew bone will grow, gradually replacing the carrier matrix as the targetsite heals. Examples of suitable carrier matrices may include, but arenot limited to, the MasterGraft® Matrix produced by Medtronic SofamorDanek, Inc., Memphis, Tenn.; MasterGraft® Putty produced by MedtronicSofamor Danek, Inc., Memphis, Tenn.; Absorbable Collagen Sponge (“ACS”)produced by Integra LifeSciences Corporation, Plainsboro, N.J.; bovineskin collagen fibers coated with hydroxyapatite, e.g. Healos® marketedby Johnson & Johnson, USA; collagen sponges, e.g. Hemostagene® marketedby Coletica S A, France, or e.g. Helisat® marketed by Integra LifeSciences Inc., USA; and Collagraft® Bone Graft Matrix produced by ZimmerHoldings, Inc., Warsaw, Ind. These carrier matrices can be modified tobe flowable for use in the device.

In some embodiments, the pharmaceutical composition comprises one ormore known members of the BMP family including, but not limited to,BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-15, BMP-16, BMP-17, BMP-18 as well aspolynucleotides or polypeptides thereof, as well as mature polypeptidesor polynucleotides encoding the same.

In various embodiments, the pharmaceutical composition can comprise adrug depot. A “drug depot” is the composition in which at least oneanti-inflammatory agent and/or at least one analgesic agent or thepharmaceutically acceptable salts of either or both are administered tothe body. Thus, a drug depot may comprise a physical structure tofacilitate implantation and retention in a desired site (e.g., a discspace, a spinal canal, a tissue of the patient, particularly at or neara site of surgery, pain, or site of inflammation, etc.). The drug depotalso comprises the drug itself. The term “drug” as used herein isgenerally meant to refer to any substance that alters the physiology ofa patient. The term “drug” may be used interchangeably herein with theterms “therapeutic agent,” “therapeutically effective amount,” and“active pharmaceutical ingredient” or “API.”

It will be understood that unless otherwise specified a “drug”formulation may include more than one therapeutic agent, whereinexemplary combinations of therapeutic agents include a combination oftwo or more drugs. The drug provides a concentration gradient of thetherapeutic agent for delivery to the site. In various embodiments, thedrug depot provides an optimal drug concentration gradient of thetherapeutic agent at a distance of up to about 0.1 cm to about 5 cm fromthe implant site, and comprises at least one anti-inflammatory agent orits pharmaceutically acceptable salt and/or at least one analgesic agentor its pharmaceutically acceptable salt.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

In some embodiment, the pharmaceutical composition comprises ananalgesic or an anti-inflammatory agent. The phrase “anti-inflammatoryagent” refers to an agent or compound that has anti-inflammatoryeffects. These agents may remedy pain by reducing inflammation.Anti-inflammatory agents also include those agents in a differentclassification with anti-inflammatory properties, such as, for example,amitriptyline, carbamazepine, gabapentin, pregabalin, clonidine, orother alpha adrenergic receptor agonist or a combination thereof.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the pharmaceutical composition results in alterationof the biological activity, such as, for example, inhibition ofinflammation, reduction or alleviation of pain, improvement in thecondition, etc. The dosage administered to a patient can unlessotherwise specified or apparent from context be as single or multipledoses depending upon a variety of factors, including the pharmaceuticalcomposition's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. In some embodiments thepharmaceutical composition is designed for immediate release. In otherembodiments the pharmaceutical composition is designed for sustainedrelease. In other embodiments, the pharmaceutical composition comprisesone or more immediate release surfaces and one or more sustain releasesurfaces.

In some embodiments, the pharmaceutical composition comprises one ormore antimicrobials, antibiotics, antimyobacterial, antifungals,antivirals, antineoplastic agents, antitumor agents, agents affectingthe immune response, blood calcium regulators, agents useful in glucoseregulation, anticoagulants, antithrombotics, antihyperlipidemic agents,cardiac drugs, thyromimetic and antithyroid drugs, adrenergics,antihypertensive agents, cholnergics, anticholinergics, antispasmodics,antiulcer agents, skeletal and smooth muscle relaxants, prostaglandins,general inhibitors of the allergic response, antihistamines, localanesthetics, analgesics, narcotic antagonists, antitussives,sedative-hypnotic agents, anticonvulsants, antipsychotics, anti-anxietyagents, antidepressant agents, anorexigenlcs, non-steroidalanti-inflammatory agents, steroidal anti-inflammatory agents,antioxidants, vaso-active agents, bone-active agents, osteogenicfactors, osteoinductive factors, antiarthritics, diagnostic agents or acombination thereof.

In various embodiments, the pharmaceutical composition can beadministered by injection. Injection includes administration that isintravenous, intramuscular, through continuous or intermittent infusion,intraperitoneal, intrasternal, subcutaneous, intra-operatively,intrathecally, intradiskally, peridiskally, epidurally, perispinally,intra-articularly or a combination thereof. Injection also includesadministration of a pharmaceutical composition in a immediate release orbolus dose or sustained or controlled release delivery.

In various embodiments, the device described herein is packaged in akit. The kit may include additional parts along with the device, forexample, disposable cannulas, drug depots, etc. The kit may include asyringe, needle, cannula and/or tube in one compartment and the housingcontaining the valve assembly. The third compartment may include thepharmaceutical composition, gloves, drapes, wound dressings and otherprocedural supplies for maintaining sterility, as well as an instructionbooklet and a DVD showing how the device operates. A fourth compartmentmay include additional cannulas and/or needles. Each tool may beseparately packaged in a plastic pouch that is radiation sterilized. Afifth compartment may include an agent for radiographic imaging. A coverof the kit may include illustrations of the ultrasonic probe procedureand a clear plastic cover may be placed over the compartments tomaintain sterility.

Methods

In some embodiments, a method is provided for limiting or reducingpressure from a pharmaceutical composition on injection at or near atarget tissue site, the method comprising injecting the pharmaceuticalcomposition at or near the target tissue site using a syringe having abarrel, the barrel having a proximal end and a distal end, the barrelcomprising a plunger being slidably receivable within the barrel topressurize and expel the pharmaceutical composition contained in thebarrel out the distal end of the barrel; a housing coupled to the distalend of the barrel of the syringe and configured to receive pressure andthe composition from the barrel when the plunger is slid, the housinghaving an inlet, an outlet and a fluid path disposed therebetween, thefluid path in fluid communication with the inlet and the outlet, a valveassembly disposed between the inlet and outlet and contacting the fluidpath and having a chamber comprising a diaphragm movable in at least aclosed position to prevent flow of the composition to the outlet and anactuator disposed in the chamber, the actuator responsive to pressure inthe fluid path and coupled to the diaphragm in the chamber, the actuatormovable in at least an upper position when a select pressure is reachedin the fluid path, wherein movement of the actuator in the upperposition moves the diaphragm in the chamber to the closed position toprevent flow of the composition.

In some embodiments, the devices and methods described herein areutilized in the diagnosis and treatment of vertebral abnormalities, suchas, compression fractures, pars defects, vertebral instability, softtissue abnormalities in ligaments, tendons, annulus, muscles,cartilaginous structures, joints (e.g., facet joints, intervertebraldiscs, sacroiliac joints, etc.) or abnormalities resulting from tumors,infection or other infiltrative processes, nerve root lesions (e.g.,compressive lesions from adjacent discs, hypertrophic facet joints,facet joints cysts, faulty hardware positioning, bony foraminalencroachment, spondylolisthesis, spondylolysis, congenitally shortpedicles, nerve sheath tumors, granulation tissue and/or arachnoiditis,etc.), spinal nerve compression (e.g., spinal stenosis), peripheralnerve lesions, femoral neuropathy, meralgia paresthetica, peronealneuropathy, asymmetrical neuropathies, lower limb joint pathology,vascular pathology, degenerative disc and joint disease or the like.

In some embodiments, the devices and methods of the current applicationcan be used to treat conditions including rheumatoid arthritis,osteoarthritis, spinal disc annular tear or herniation (e.g., sciatica),carpal/tarsal tunnel syndrome, lower back pain, discogenic back pain,lower extremity pain, upper extremity pain, cancer, tissue pain and painassociated with injury or repair of cervical, thoracic, and/or lumbarvertebrae or intervertebral discs, rotator cuff, articular joint, TMJ,tendons, ligaments, muscles, spondilothesis, stenosis, or joint pain orthe like.

In some embodiments, the devices and methods described herein areutilized in the diagnosis and treatment of back pain from, for example,a herniated disc, or spinal stenosis. Typically, when a patient has aherniated disc, the patient will exhibit severe or persistent radicularpain. When the herniated disc is in the lower back, persistent pain canoriginate in the back and often extends (“radiates”) into the leg alongthe distribution of the sciatic nerve (lumbar radicular pain, orsciatica). In patients with herniated disc in the neck, the persistentpain can originate in the neck and often radiates into the arm. Thedevices and methods of the present application can assist thepractitioner in diagnosing and providing treatment for such condition.

Spinal stenosis is another condition where the patient will exhibit,among other things, back pain. Spinal stenosis, either acquired orcongenital, results from degenerative changes in the spine, variablyincluding the intervertebral disks, the intervertebral joints (facetjoints) and the ligamentum flavum. In each case, the degenerativechanges together result in a gradual narrowing of the lumbar or cervicalspinal canal, causing compression of the spinal cord and spinal nerveroots. Symptoms include: pain and/or numbness in the neck, back,buttocks, legs, thighs or calves that is worse with walking, standingand/or exercise; back pain that radiates to the legs; weakness of thelegs; and difficulty or imbalance when walking. Patients can bediagnosed with spinal stenosis through, for example, persistentradiating pain; neurologic examination findings of abnormal sensationand muscle weakness in the legs; gait disturbances and characteristicbent over posture; asymmetric deep tendon reflexes; and radiologicfindings of spinal stenosis by x-ray (e.g., myelogram), MRI, spinal CTor CT myelography or the like. Depending on whether the stenosis iscentral or foraminal, provocative maneuvers on physical examination suchas side bending reproducing the pain may be negative or positive,respectively. The devices and methods of the present application canassist the practitioner in diagnosing and providing treatment for suchcondition.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. An injection shut off valve for limiting flow of a composition, theshut off valve comprising: a housing having an inlet, an outlet and aflow path disposed therebetween and in fluid communication with theinlet and the outlet, the inlet configured to receive an end of aninjection syringe; and a valve assembly contacting the flow path andhaving a first chamber and a second chamber, the first chambercomprising a diaphragm movable in at least a closed position to preventflow of the composition to the outlet, the second chamber having anactuator disposed therein, the actuator responsive to pressure in theflow path and coupled to the diaphragm in the first chamber, theactuator movable in at least an upper position when a select pressure isreached in the flow path, wherein movement of the actuator in the upperposition moves the diaphragm in the first chamber to the closed positionto prevent flow of the composition, and the actuator further comprises alever that contacts the diaphragm and releases the diaphragm when theactuator is moved in the upper position to prevent flow to the outlet.2. An injection shut off valve according to claim 1, wherein thediaphragm and actuator are substantially perpendicular to the flow path.3. An injection shut off valve according to claim 1, wherein the selectpressure does not exceed a maximum pressure that causes damage to atissue of a patient.
 4. An injection shut off valve according to claim1, wherein the inlet is connected to a syringe containing thecomposition that is a liquid, or semisolid and the outlet is connectedto a needle, cannula or flexible tubing.
 5. An injection shut off valveaccording to claim 1, wherein the diaphragm is movable in an openposition to allow flow to the outlet when the actuator is in a lowerposition and the pressure in the flow path is less than the selectpressure.
 6. An injection shut off valve according to claim 1, wherein(i) the diaphragm has a surface that contacts an elastic member disposedin the first chamber that holds the diaphragm in the closed position toprevent flow of the composition or (ii) the actuator has a surface thatcontacts an elastic member disposed in the second chamber that pushesthe actuator in a lower position moving the diaphragm in an openposition to allow flow of the composition.
 7. An injection shut offvalve according to claim 1, wherein the diaphragm moves incrementally tothe closed position to prevent flow to the outlet.
 8. An injection shutoff valve according to claim 1, wherein the diaphragm and/or actuator iscoupled to a gauge having indicators to measure the pressure.
 9. Adevice for delivering a pharmaceutical composition to a target tissue,the apparatus comprising: a syringe having a barrel, the barrel having aproximal end and a distal end, the barrel comprising a plunger beingslidably receivable within the barrel to pressurize and expel thepharmaceutical composition contained in the barrel out the distal end ofthe barrel; a housing coupled to the distal end of the barrel of thesyringe and configured to receive pressure and the composition from thebarrel when the plunger is slid, the housing having an inlet, an outletand a fluid path disposed therebetween, the fluid path in fluidcommunication with the inlet and the outlet; and a valve assemblydisposed between the inlet and outlet and contacting the fluid path andhaving a first chamber comprising a diaphragm movable in at least aclosed position to prevent flow of the composition to the outlet and anactuator disposed in a second the chamber, the actuator responsive topressure in the fluid path and coupled to the diaphragm in the firstchamber, the actuator movable in at least an upper position when aselect pressure is reached in the fluid path, wherein movement of theactuator in the upper position moves the diaphragm in the first chamberto the closed position to prevent flow of the composition, wherein theactuator further comprises a lever that contacts the diaphragm andreleases the diaphragm when the actuator is moved in the upper positionto prevent flow to the outlet.
 10. A device according to claim 9,wherein the diaphragm and actuator are substantially perpendicular tothe fluid path.
 11. A device according to claim 9, wherein the selectpressure does not exceed a maximum pressure that causes damage to thetarget tissue of a patient.
 12. A device according to claim 9, whereinthe outlet is connected to a needle, cannula or flexible tubing.
 13. Adevice according to claim 9, wherein the diaphragm is smaller, the samesize or larger than the diameter of the fluid path and the diaphragm ismovable in an open position to allow the composition to flow to theoutlet, when the actuator is in a lower position and the pressure islower than the select pressure.
 14. A device according to claim 9,wherein (i) the diaphragm contacts an elastic member disposed in thefirst chamber that holds the diaphragm in the closed position to preventflow of the composition or (ii) the actuator contacts an elastic memberdisposed in the first chamber that pushes the actuator in a lowerposition moving the diaphragm in an open position to allow flow of thecomposition.
 15. A device according to claim 9, wherein (i) thediaphragm moves incrementally to the closed position to prevent thecomposition flow to the outlet; or (ii) the diaphragm and/or actuator iscoupled to a gauge having indicators to measure the pressure.
 16. Adevice according to claim 9, wherein the pharmaceutical compositioncomprises a liquid, solid, or semisolid.
 17. A method for limitingpressure from a pharmaceutical composition on injection at or near atarget tissue site, the method comprising injecting the pharmaceuticalcomposition at or near the target tissue site using a syringe having abarrel, the barrel having a proximal end and a distal end, the barrelcomprising a plunger being slidably receivable within the barrel topressurize and expel the pharmaceutical composition contained in thebarrel out the distal end of the barrel; a housing coupled to the distalend of the barrel of the syringe and configured to receive pressure andthe composition from the barrel when the plunger is slid, the housinghaving an inlet, an outlet and a fluid path disposed therebetween, thefluid path in fluid communication with the inlet and the outlet, a valveassembly disposed between the inlet and outlet and contacting the fluidpath and having a first chamber comprising a diaphragm movable in atleast a closed position to prevent flow of the composition to the outletand an actuator disposed in a second chamber, the actuator responsive topressure in the fluid path and coupled to the diaphragm in the firstchamber, the actuator movable in at least an upper position when aselect pressure is reached in the fluid path, wherein movement of theactuator in the upper position moves the diaphragm in the first chamberto the closed position to prevent flow of the composition, and theactuator further comprises a lever that contacts the diaphragm andreleases the diaphragm when the actuator is moved in the upper positionto prevent flow to the outlet.
 18. A method according to claim 17,wherein a needle or cannula is coupled to the outlet of the housing. 19.A method according to claim 17, wherein (i) the pharmaceuticalcomposition comprises a liquid, solid, or semisolid; or (ii) the targettissue site is an intervertebral disc; or (iii) the pressure oninjection does not exceed (iii) about 100 to about 140 psi or (iv) 120psi or (v) about 10 to about 20 psi in a needle or cannula that iscoupled to the outlet of the housing.
 20. An injection shut off valvefor limiting flow of a composition, the shut off valve comprising: ahousing having an inlet, an outlet and a flow path disposed therebetweenand in fluid communication with the inlet and the outlet, the inletconfigured to receive an end of an injection syringe; and a valveassembly contacting the flow path and having a first chamber and asecond chamber, the first chamber comprising a diaphragm movable in atleast a closed position to prevent flow of the composition to theoutlet, the second chamber having an actuator disposed therein, theactuator responsive to pressure in the flow path and coupled to thediaphragm in the first chamber, the actuator movable in at least anupper position when a select pressure is reached in the flow path,wherein movement of the actuator in the upper position moves thediaphragm in the first chamber to the closed position to prevent flow ofthe composition and the diaphragm and actuator are substantiallyperpendicular to the flow path.
 21. An injection shut off valveaccording to claim 20, wherein the select pressure does not exceed amaximum pressure that causes damage to a tissue of a patient.
 22. Aninjection shut off valve according to claim 20, wherein the inlet isconnected to a syringe containing the composition that is a liquid, orsemisolid and the outlet is connected to a needle, cannula or flexibletubing.
 23. An injection shut off valve according to claim 20, whereinthe diaphragm is movable in an open position to allow flow to the outletwhen the actuator is in a lower position and the pressure in the flowpath is less than the select pressure.
 24. An injection shut off valveaccording to claim 20, wherein the diaphragm moves incrementally to theclosed position to prevent flow to the outlet.
 25. An injection shut offvalve according to claim 20, wherein the diaphragm and/or actuator iscoupled to a gauge having indicators to measure the pressure.